Dilated cardiomyopathy (DC) represents an important cause of cardiovascular morbidity and mortality and consumes a disproportionate share of medical resources in this country. Despite recent advances in the treatment of DC, this disorder has a poor prognosis with 5 year mortality rates of 20-50 percent. Progress in understanding the pathophysiology of DC and in devising new therapies for this disorder has been limited by our relative lack of understanding of the molecular pathophysiology of the disease and by the lack of a small animal model which closely resembles the anatomical, physiological, and clinical features of the human disease. We have recently shown that transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac-specific alpha-MHC promoter reproducibly develop DC that resembles many of the anatomical, physiological and clinical features of human DC. In the studies described in these 3 collaborative R01 applications we propose to use this new mouse model to better understand the molecular pathways by which CREB regulates cardiac myocyte homeostasis and how perturbations in these pathways produce DC. Specifically we will 1) elucidate the CREB-dependent signaling pathways that are required to maintain cardiac myocyte homeostasis and determine how these pathways are perturbed in the CREBA133 mice with DC, 2) determine the role of apoptosis in the CREBAl33 DC and test the hypothesis that the cardiomyopathic phenotype can be ameliorated by expression of anti-apoptotic genes in the heart, 3) study excitation-contraction coupling, contractility, and calcium homestasis in the CREBA133 cardiac myocytes, 4) understand the myofibrillar and SR defects underlying cardiac myocyte dysfunction in the CREBA133 mice, 5) study ventricular remodeling and LV-arterial coupling during the development of DC in the CREBA133 mice, and 6) determine the effects of exercise conditioning, gender, and different modes of inhibiting the renin angiotensin system on progression of DC in the CREBA133 mice. These studies represent the continuation of an established collaboration between molecular biologists (Leiden), cell physiologists (Moss) mouse and human physiologists (Lang, Spencer) and clinical cardiologists (Leiden, Lang, Spencer) the Universities of Chicago and Wisconsin. Taken together the results of this work should provide us with important new insights into the molecular mechanisms underlying human DC and CHF.